Acute megakaryoblastic leukaemia shows high frequency of chromosome 1q aberrations and dismal outcome.

Acute megakaryoblastic leukaemia (AMKL) is associated with poor prognosis. Limited information is available on its cytogenetics, molecular genetics and clinical outcome. We performed genetic analyses, evaluated prognostic factors and the value of allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a homogenous adult AMKL patient cohort. We retrospectively analysed 38 adult patients with AMKL (median age: 58 years, range: 21-80). Most received intensive treatment in AML Cooperative Group (AMLCG) trials between 2001 and 2016. Cytogenetic data showed an accumulation of adverse risk markers according to ELN 2017 and an unexpected high frequency of structural aberrations on chromosome arm 1q (33%). Most frequently, mutations occurred in TET2 (23%), TP53 (23%), JAK2 (19%), PTPN11 (19%) and RUNX1 (15%). Complete remission rate in 33 patients receiving intensive chemotherapy was 33% and median overall survival (OS) was 33 weeks (95% CI: 21-45). Patients undergoing allo-HSCT (n = 14) had a superior median OS (68 weeks; 95% CI: 11-126) and relapse-free survival (RFS) of 27 weeks (95% CI: 4-50), although cumulative incidence of relapse after allo-HSCT was high (62%). The prognosis of AMKL is determined by adverse genetic risk factors and therapy resistance. So far allo-HSCT is the only potentially curative treatment option in this dismal AML subgroup.

Molecular Landscape of Tourette's Disorder.

Tourette's disorder (TD) is a highly heritable childhood-onset neurodevelopmental disorder and is caused by a complex interplay of multiple genetic and environmental factors. Yet, the molecular mechanisms underlying the disorder remain largely elusive. In this study, we used the available omics data to compile a list of TD candidate genes, and we subsequently conducted tissue/cell type specificity and functional enrichment analyses of this list. Using genomic data, we also investigated genetic sharing between TD and blood and cerebrospinal fluid (CSF) metabolite levels. Lastly, we built a molecular landscape of TD through integrating the results from these analyses with an extensive literature search to identify the interactions between the TD candidate genes/proteins and metabolites. We found evidence for an enriched expression of the TD candidate genes in four brain regions and the pituitary. The functional enrichment analyses implicated two pathways ('cAMP-mediated signaling' and 'Endocannabinoid Neuronal Synapse Pathway') and multiple biological functions related to brain development and synaptic transmission in TD etiology. Furthermore, we found genetic sharing between TD and the blood and CSF levels of 39 metabolites. The landscape of TD not only provides insights into the (altered) molecular processes that underlie the disease but, through the identification of potential drug targets (such as FLT3, NAALAD2, CX3CL1-CX3CR1, OPRM1, and HRH2), it also yields clues for developing novel TD treatments.

Molecular landscape of thymic epithelial tumors.

Thymic epithelial tumors (TETs) are extremely rare and represent the most frequent tumors of the anterior mediastinum originating from epithelial cells in the thymus. Thymic epithelial tumors include thymomas (TM), thymic carcinomas (TC) and thymic neuroendocrine neoplasms (TNEN). Thymomas are the most predominant and are associated with autoimmune diseases. The available data suggests that the different histological subtypes have specific molecular alterations. Thymic carcinoma shows recurrent gene mutations, but further investigations are needed to understand the role of those mutations in the pathogenetic of the TETs. Some of the new emerging identified molecular alterations have the potential to offer new targeted therapies opening new possibilities for the treatment of thymic epithelial tumors.

Novel Molecular Insights into Leukemic Evolution of Myeloproliferative Neoplasms: A Single Cell Perspective.

Myeloproliferative neoplasms (MPNs) are clonal disorders originated by the serial acquisition of somatic mutations in hematopoietic stem/progenitor cells. The major clinical entities are represented by polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), that are caused by driver mutations affecting JAK2, MPL or CALR. Disease progression is related to molecular and clonal evolution. PV and ET can progress to secondary myelofibrosis (sMF) but can also evolve to secondary acute myeloid leukemia (sAML). PMF is associated with the highest frequency of leukemic transformation, which represents the main cause of death. sAML is associated with a dismal prognosis and clinical features that differ from those of de novo AML. The molecular landscape distinguishes sAML from de novo AML, since the most frequent hits involve TP53, epigenetic regulators, spliceosome modulators or signal transduction genes. Single cell genomic studies provide novel and accurate information about clonal architecture and mutation acquisition order, allowing the reconstruction of clonal dynamics and molecular events that accompany leukemic transformation. In this review, we examine our current understanding of the genomic heterogeneity in MPNs and how it affects disease progression and leukemic transformation. We focus on molecular events elicited by somatic mutations acquisition and discuss the emerging findings coming from single cell studies.

Molecular, genomic and mutational landscape of oral leukoplakia.

Oral leukoplakia (OLK) and its more aggressive clinical variant proliferative verrucous leukoplakia (PVL) remain enigmatic disorders clinically and histopathologically. Despite decades of research into both, there has been only incremental advancement in our understanding of their aetiology and pathogenesis and only minimal improvement in effective management strategies. Currently, no specific prognostic genetic or molecular marker has been reported for leukoplakia. There is, however, an emerging body of evidence characterising the genomic and transcriptomic profile of OLK. Regardless of the significance of cellular and architectural features of OLK and PVL, it is clear from studies reported in this review that new emerging evidence points to the presence of premalignant molecular subtypes of leukoplakia which require further investigation. This up-to-date review explores the contemporary genomic, transcriptomic and mutational landscape of leukoplakia broadly, discusses concepts that may not be widely recognised or accepted and purposefully highlights studies with juxtaposed findings in an effort to challenge dogma. It also highlights the urgent need for a concerted international effort of original collaborative research which will only occur by pooling collective efforts, resources and intellect to define the molecular fingerprint of this enigmatic disorder, in the hope it will better inform diagnosis, stratification and treatment.

Philadelphia-Negative MPN: A Molecular Journey, from Hematopoietic Stem Cell to Clinical Features.

Philadelphia negative Myeloproliferative Neoplasms (MPN) are a heterogeneous group of hematopoietic stem cell diseases. MPNs show different risk grades of thrombotic complications and acute myeloid leukemia evolution. In the last couple of decades, from JAK2 mutation detection in 2005 to the newer molecular trademarks studied through next generation sequencing, we are learning to approach MPNs from a deeper perspective. Here, we intend to elucidate the important factors affecting MPN clonal advantage and the reasons why some patients progress to more aggressive disease. Understanding these mechanisms is the key to developing new treatment approaches and targeted therapies for MPN patients.

Genetic Markers in Lung Cancer Diagnosis: A Review.

Lung cancer is the most often diagnosed cancer in the world and the most frequent cause of cancer death. The prognosis for lung cancer is relatively poor and 75% of patients are diagnosed at its advanced stage. The currently used diagnostic tools are not sensitive enough and do not enable diagnosis at the early stage of the disease. Therefore, searching for new methods of early and accurate diagnosis of lung cancer is crucial for its effective treatment. Lung cancer is the result of multistage carcinogenesis with gradually increasing genetic and epigenetic changes. Screening for the characteristic genetic markers could enable the diagnosis of lung cancer at its early stage. The aim of this review was the summarization of both the preclinical and clinical approaches in the genetic diagnostics of lung cancer. The advancement of molecular strategies and analytic platforms makes it possible to analyze the genome changes leading to cancer development-i.e., the potential biomarkers of lung cancer. In the reviewed studies, the diagnostic values of microsatellite changes, DNA hypermethylation, and p53 and KRAS gene mutations, as well as microRNAs expression, have been analyzed as potential genetic markers. It seems that microRNAs and their expression profiles have the greatest diagnostic potential value in lung cancer diagnosis, but their quantification requires standardization.

Exploring the molecular landscape of osteosarcoma through PTTG family genes using a detailed multi-level methodology.

Background: Osteosarcoma (OS) poses a significant clinical challenge, necessitating a comprehensive exploration of its molecular underpinnings. Methods: This study explored the roles of PTTG family genes (PTTG1, PTTG2, and PTTG3P) in OS, employing a multifaceted approach encompassing molecular experiments, including OS cell lines culturing, RT-qPCR, bisulfite and Whole Exome Sequencing (WES) and in silico experiments, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets-based validation, overall survival, gene enrichment, functional assays, and molecular docking analyses. Results: Our findings reveal a consistent up-regulation of PTTG genes in OS cell lines, supported by RT-qPCR experiments and corroborated across various publically available expression datasets databases. Importantly, ROC curve analyses highlight their potential as diagnostic markers. Moving beyond expression profiles, we unveil the epigenetic landscape by demonstrating significant hypomethylation of CpG islands associated with PTTG genes in OS. The negative correlation between methylation status and mRNA expression emphasizes the regulatory role of promoter methylation in PTTG gene expression. Contrary to expectations, genetic mutations in PTTG genes are rare in OS, with only benign mutations observed. Moreover, functional assays also confirmed the oncogenic roles of the PTTG gene in the development of OS. Lastly, we also revealed that Calcitriol is the most appropriate drug that can be utilized to treat OS in the context of PTTG genes. Conclusion: The identification of PTTG genes as potential diagnostic markers and their association with epigenetic alterations opens new avenues for understanding OS pathogenesis and developing targeted therapies. As we navigate the complex landscape of OS, this study contributes essential insights that may pave the way for improved diagnostic and therapeutic strategies in its management.

Clinical features and molecular landscape of cuproptosis signature-related molecular subtype in gastric cancer.

Recent studies have highlighted the biological significance of cuproptosis in disease occurrence and development. However, it remains unclear whether cuproptosis signaling also has potential impacts on tumor initiation and prognosis of gastric cancer (GC). In this study, 16 cuproptosis-related genes (CRGs) transcriptional profiles were harnessed to perform the regularized latent variable model-based clustering in GC. A cuproptosis signature risk scoring (CSRS) scheme, based on a weighted sum of principle components of the CRGs, was used to evaluate the prognosis and risk of individual tumors of GC. Four distinct cuproptosis signature-based clusters, characterized by differential expression patterns of CRGs, were identified among 1136 GC samples across three independent databases. The four clusters were also associated with different clinical outcomes and tumor immune contexture. Based on the CSRS, GC patients can be divided into CSRS-High and CSRS-Low subtypes. We found that DBT, MTF1, and ATP7A were significantly elevated in the CSRS-High subtype, while SLC31A1, GCSH, LIAS, DLAT, FDX1, DLD, and PDHA1 were increased in the CSRS-Low subtype. Patients with CSRS-Low score were characterized by prolonged survival time. Further analysis indicated that CSRS-Low score also correlated with greater tumor mutation burden (TMB) and higher mutation rates of significantly mutated genes (SMG) in GC. In addition, the CSRS-High subtype harbored more significantly amplified focal regions related to tumorigenesis (3q27.1, 12p12.1, 11q13.3, etc.) than the CSRS-Low tumors. Drug sensitivity analyses revealed the potential compounds for the treatment of gastric cancer with CSRS-High score, which were experimentally validated using GC cells. This study highlights that cuproptosis signature-based subtyping is significantly associated with different clinical features and molecular landscape of GC. Quantitative evaluation of the CSRS of individual tumors will strengthen our understanding of the occurrence and development of cuproptosis and the treatment progress of GC.

Molecular profiling of biliary tract cancers reveals distinct genomic landscapes between circulating and tissue tumor DNA.

Biliary tract cancers (BTCs) are heterogeneous malignancies with dismal prognosis due to tumor aggressiveness and poor response to limited current therapeutic options. Tumor exome profiling has allowed to successfully establish targeted therapeutic strategies in the clinical management of cholangiocarcinoma (CCA). Still, whether liquid biopsy profiling could inform on BTC biology and patient management is unknown. In order to test this and generate novel insight into BTC biology, we analyzed the molecular landscape of 128 CCA patients, using a 394-gene NGS panel (Foundation Medicine). Among them, 32 patients had matched circulating tumor (ct) DNA and tumor DNA samples, where both samples were profiled. In both tumor and liquid biopsies, we identified an increased frequency of alterations in genes involved in genome integrity or chromatin remodeling, including ARID1A (15%), PBRM1 (9%), and BAP1 (14%), which were validated using an in-house-developed immunohistochemistry panel. ctDNA and tumor DNA showed variable concordance, with a significant correlation in the total number of detected variants, but some heterogeneity in the detection of actionable mutations. FGFR2 mutations were more frequently identified in liquid biopsies, whereas KRAS alterations were mostly found in tumors. All IDH1 mutations detected in tumor DNA were also identified in liquid biopsies. These findings provide novel insights in the concordance between the tumor and liquid biopsies genomic landscape in a large cohort of patients with BTC and highlight the complementarity of both analyses when guiding therapeutic prescription.

Pathogenic variants of mycosis fungoides identified using next-generation sequencing.

Mycosis fungoides (MF), the predominant form of cutaneous T-cell lymphoma (CTCL), poses diagnostic challenges due to its clinical and histological resemblance to benign skin disorders. Delayed diagnosis contributes to therapeutic delays, prompting exploration of advanced diagnostics tools. Next-generation sequencing (NGS) may enhance disease detection by identifying pathogenic variants common to CTCL but absent in benign inflammatory disorders. We aim to discuss novel and common pathogenic variants in CTCL to enhance the utility of NGS as a diagnostic adjunct. This pilot study employed (NGS) to identify pathogenic variants in 10 MF cases. Cases were selected based on PCR-confirmed T-cell receptor clonality, with adequate DNA for NGS. GatorSeq NGS Panel, Illumina NextSeq500, and QIAGEN Clinical Insight QCI software facilitated sequencing, analysis, and variant interpretation. NGS revealed eight novel mutations in genes including HLA-DRB1, AK2, ITPKB, HLA-B, TYRO3, and CHD2. Additionally, previously reported MF-associated mutations such as DNMT3A, STAT5B, and SOCS1 (mouse study only) were detected as well. Detected variants were involved in apoptotic, NF-kB, JAK-STAT, and TCR signaling pathways, providing insights into MF pathogenesis. Mutations in genes like APC, AK2, TYRO3, and ITPKB that regulate tumor proliferation and apoptosis were noted. MF cases were associated with HLA gene mutations. NGS may enhance MF diagnosis, as the detection of pathogenic variants, particularly those known to occur in MF, favors a neoplastic diagnosis over an inflammatory diagnosis. Continuing this work may lead to the discovery of therapeutic targets.

Advances in next-generation sequencing for relapsed pediatric acute lymphoblastic leukemia: current insights and future directions.

Leukemia is one of the most common cancers in children; and its genetic diversity in the landscape of acute lymphoblastic leukemia (ALL) is important for diagnosis, risk assessment, and therapeutic approaches. Relapsed ALL remains the leading cause of cancer deaths among children. Almost 20% of children who are treated for ALL and achieve complete remission experience disease recurrence. Relapsed ALL has a poor prognosis, and relapses are more likely to have mutations that affect signaling pathways, chromatin patterning, tumor suppression, and nucleoside metabolism. The identification of ALL subtypes has been based on genomic alterations for several decades, using the molecular landscape at relapse and its clinical significance. Next-generation sequencing (NGS), also known as massive parallel sequencing, is a high-throughput, quick, accurate, and sensitive method to examine the molecular landscape of cancer. This has undoubtedly transformed the study of relapsed ALL. The implementation of NGS has improved ALL genomic analysis, resulting in the recent identification of various novel molecular entities and a deeper understanding of existing ones. Thus, this review aimed to consolidate and critically evaluate the most current information on relapsed pediatric ALL provided by NGS technology. In this phase of targeted therapy and personalized medicine, identifying the capabilities, benefits, and drawbacks of NGS will be essential for healthcare professionals and researchers offering genome-driven care. This would contribute to precision medicine to treat these patients and help improve their overall survival and quality of life.

Neuroendocrine Neoplasms: Genetics and Epigenetics.

Neuroendocrine neoplasms (NENs) are a group of rare, heterogeneous tumors of neuroendocrine cell origin, affecting a range of different organs. The clinical management of NENs poses significant challenges, as tumors are often diagnosed at an advanced stage where overall survival remains poor with current treatment regimens. In addition, a host of complex and often unique molecular changes underpin the pathobiology of each NEN subtype. Exploitation of the unique genetic and epigenetic signatures driving each NEN subtype provides an opportunity to enhance the diagnosis, treatment, and monitoring of NEN in an emerging era of individualized medicine.

Gynecological carcinosarcomas: Overview and future perspectives.

Gynecologic carcinosarcoma (CS) are rare and aggressive tumors composed of high-grade carcinoma and sarcoma. Carcinosarcoma account for less than 5% of uterine and ovarian carcinoma and patients have poor outcome with a 5-year overall survival of less than 30%. In early-stage setting, the treatment mainstay is surgery and adjuvant chemoradiotherapy or adjuvant chemotherapy in uterine (UCS) and ovarian CS (OCS), respectively. In metastatic or advanced stage disease, chemotherapy is the rule with a lower response rate and poorer prognosis compared to other high-grade carcinomas. Although very few treatment options are available, CS are often excluded from the clinical trials precluding therapeutic improvement. However, recent molecular advances are paving the way for new therapeutic strategies. In the current proposal, we extensively review the uterine and ovarian carcinosarcomas including epidemiology, pathology, genomic landscape, as well as current therapies and future perspectives.

Systemic Therapy for Advanced Hepatocellular Carcinoma: Current Stand and Perspectives.

Hepatocellular carcinoma often develops in the context of chronic liver disease. It is the sixth most frequently diagnosed cancer and the third most common cause of cancer-related mortality worldwide. Although the mainstay of therapy is surgical resection, most patients are not eligible because of liver dysfunction or tumor extent. Sorafenib was the first tyrosine kinase inhibitor that improved the overall survival of patients who failed to respond to local therapies or had advanced disease, and for many years, it was the only treatment approved for the first-line setting. However, in recent years, trials have demonstrated an improvement in survival with treatments based on immunotherapy and new targeting agents, thereby extending the treatment options. A phase III trial showed that a combination of immunotherapy and targeted therapy, including atezolizumab plus bevacizumab, improved survival in the first-line setting, and is now considered the new standard of care. Other agents and combinations are being tested, including the combination of nivolumab plus ipilimumab and tremelimumab plus durvalumab, and they reportedly have clinical benefits. The aim of this manuscript is to review the latest approved therapeutic options in first- and second-line settings for advanced HCC and discuss future perspectives.

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression.

Introduction: Glioblastoma (GBM) is notorious for its clinical and molecular heterogeneity, contributing to therapeutic failure and a grim prognosis. WWOX is one of the tumor suppressor genes important in nervous tissue or related pathologies, which was scarcely investigated in GBM for reliable associations with prognosis or disease progression despite known alterations. Recently, we observed a phenotypic heterogeneity between GBM cell lines (U87MG, T98G, U251MG, DBTRG-05MG), among which the anti-GBM activity of WWOX was generally corresponding, but colony growth and formation were inconsistent in DBTRG-05MG. This prompted us to investigate the molecular landscapes of these cell lines, intending to translate them into the clinical context. Methods: U87MG/T98G/U251MG/DBTRG-05MG were subjected to high-throughput sequencing, and obtained data were explored via weighted gene co-expression network analysis, differential expression analysis, functional annotation, and network building. Following the identification of the most relevant DBTRG-distinguishing driver genes, data from GBM patients were employed for, e.g., differential expression analysis, survival analysis, and principal component analysis. Results: Although most driver genes were unique for each cell line, some were inversely regulated in DBTRG-05MG. Alongside driver genes, the differentially-expressed genes were used to build a WWOX-related network depicting protein-protein interactions in U87MG/T98G/U251MG/DBTRG-05MG. This network revealed processes distinctly regulated in DBTRG-05MG, e.g., microglia proliferation or neurofibrillary tangle assembly. POLE4 and HSF2BP were selected as DBTRG-discriminating driver genes based on the gene significance, module membership, and fold-change. Alongside WWOX, POLE4 and HSF2BP expression was used to stratify patients into cell lines-resembling groups that differed in, e.g., prognosis and treatment response. Some differences from a WWOX-related network were certified in patients, revealing genes that clarify clinical outcomes. Presumably, WWOX overexpression in DBTRG-05MG resulted in expression profile change resembling that of patients with inferior prognosis and drug response. Among these patients, WWOX may be inaccessible for its partners and does not manifest its anti-cancer activity, which was proposed in the literature but not regarding glioblastoma or concerning POLE4 and HSF2BP. Conclusion: Cell lines data enabled the identification of patients among which, despite high expression of WWOX tumor suppressor, no advantageous outcomes were noted due to the cancer-promoting profile ensured by other genes.

Comprehensive genomic characterization of sporadic synchronous colorectal cancer: Implications for treatment optimization and clinical outcome.

Sporadic synchronous colorectal cancer (SCRC) refers to multiple primary CRC tumors detected simultaneously in an individual without predisposing hereditary conditions, which accounts for the majority of multiple CRCs while lacking a profound understanding of the genomic landscape and evolutionary dynamics to optimize its treatment. In this study, 103 primary tumor samples from 51 patients with SCRC undergo whole-exome sequencing. The germline and somatic mutations and evolutionary and clinical features are comprehensively investigated. Somatic genetic events are largely inconsistent between paired tumors. Compared with solitary CRC, SCRCs have higher prevalence of tumor mutation burden high (TMB-H; 33.3%) and microsatellite-instability high (MSI-H; 29.4%) and different mutation frequencies in oncogenic signaling pathways. Moreover, neutrally evolving SCRC tumors are associated with higher intratumoral heterogeneity and better prognosis. These findings unveil special molecular features, carcinogenesis, and prognosis of sporadic SCRC. Strategies for targeted therapy and immunotherapy should be optimized accordingly.

Primary Mucinous Cystadenocarcinoma of the Breast Intermixed with Pleomorphic Invasive Lobular Carcinoma: The First Report of This Rare Association.

Primary mucinous cystadenocarcinoma (MCA) is a rare breast carcinoma subtype showing overlapping histopathological features with mucinous cystadenocarcinoma of the ovary and pancreas. Current literature data suggest a favorable prognosis of breast MCAs despite its immunoprofile usually revealing lack of expression of estrogen receptor, progesterone receptor and HER-2 and high Ki67. As far as we know, only 36 cases have been reported in the literature to date. Its ambiguous morpho-phenotypic profile makes histological diagnosis very challenging. It must be distinguished from typical mucin-producing breast carcinomas and, above all, metastases from the same histotype in other sites (ovary, pancreas, appendix). Herein, we report the case of a primary breast MCA occurring in a 41-year-old female with peculiar histological features.

ITGB1-mediated molecular landscape and cuproptosis phenotype induced the worse prognosis in diffuse gastric cancer.

Diffuse type gastric cancer was identified with relatively worse prognosis than other Lauren's histological classification. Integrin ß1 (ITGB1) was a member of integrin family which played a markedly important role in tumorigenesis and progression. However, the influence of ITGB1 in diffuse gastric cancer (DGC) remains uncertain. Here, we leveraged the transcriptomic and proteomic data to explore the association between ITGB1 expression and clinicopathologic information and biological process in DGC. Cell phenotype experiments combined with quantitative-PCR (q-PCR) and western blotting were utilized to identify the potential molecular mechanism underling ITGB1.Transcriptomics and proteomics both revealed that the higher ITGB1 expression was significantly associated with worse prognosis in DGC, but not in intestinal GC. Genomic analysis indicated that the mutation frequency of significantly mutated genes of ARID1A and COL11A1, and mutational signatures of SBS6 and SBS15 were markedly increased in the ITGB1 low expression subgroup. The enrichment analysis revealed diverse pathways related to dysregulation of ITGB1 in DGC, especially in cell adhesion, proliferation, metabolism reprogramming, and immune regulation alterations. Elevated activities of kinase-ROCK1, PKACA/PRKACA and AKT1 were observed in the ITGB1 high-expression subgroup. The ssGSEA analysis also found that ITGB1 low-expression had a higher cuproptosis score and was negatively correlated with key regulators of cuproptosis, including FDX1, DLAT, and DLST. We further observed that the upregulated expression of mitochondrial tricarboxylic acid (TCA) cycle in the ITGB1 low-expression group. Reduced expression of ITGB1 inhibited the ability of cell proliferation and motility and also potentiated the cell sensitive to copper ionophores via western blotting assay. Overall, this study revealed that ITGB1 was a protumorigenic gene and regulated tumor metabolism and cuproptosis in DGC.

NTRK fusion protein expression is absent in a large cohort of diffuse large B-cell lymphoma.

Background: Even though two NTRK-targeting drugs are available for the treatment of irresectable, metastatic, or progressive NTRK-positive solid tumors, less is known about the role of NTRK fusions in lymphoma. For this reason, we aimed to investigate if NTRK fusion proteins are expressed in diffuse large B-cell lymphoma (DLBCL) by systemic immunohistochemistry (IHC) screening and additional FISH analysis in a large cohort of DLBCL samples according to the ESMO Translational Research and Precision Medicine Working Group recommendations for the detection of NTRK fusions in daily practice and clinical research. Methods: A tissue microarray of 92 patients with the diagnosis of DLBCL at the University Hospital Hamburg between 2020 and 2022 was built. The clinical data were taken from patient records. Immunohistochemistry for Pan-NTRK fusion protein was performed and positive staining was defined as any viable staining. For FISH analysis only results with quality 2 and 3 were evaluated. Results: NTRK immunostaining was absent in all analyzable cases. No break apart was detectable by FISH. Conclusion: Our negative result is consistent with the very sparse data existing on NTRK gene fusions in hematologic neoplasms. To date, only a few cases of hematological malignancies have been described in which NTRK-targeting drugs may provide a potential therapeutic agent. Even though NTRK fusion protein expression was not detectable in our sample cohort, performing systemic screenings for NTRK fusions are necessary to define further the role of NTRK fusions not only in DLBCL but in a multitude of lymphoma entities as long as the lack of reliable data exists.